The present invention relates to an ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative which is a novel useful compound as an intermediate for the synthesis of pharmaceuticals.
This ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative is a useful compound as an intermediate commonly used for the synthesis of various HMG-CoA (3-hydroxyglutaryl coenzyme A) reductase inhibitors whose action as an anti-hyperlipemia has attracted attentions.
As a process for preparing a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative, already reported are (1) a process for diastereoseletively reducing an (S)-5,6-dihydroxy-3-oxohexanoic acid derivative with a reducing agent such as sodium borohydride and, trialkylborane or alkoxydialkylborane (JP-A-1-199945 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d), JP-A-2-262537); and (2) a process for subjecting an (S)-5,6-dihydroxy-3-oxohexanoic acid derivative to asymmetric hydrogenation in the presence of a ruthenium-optically active phosphine complex as a catalyst (JP-A-6-65226).
Many of the (3R,5S)-3,5,6-trihydroxyhexanoic acid derivatives so far reported are obtained as oily matter. It is the present situation that such crude products tend to be provided for a subsequent step without being improved into a high-purity syn-isomer.
According to the report by G. Beck, et al. (Synthesis, 1014(1995)), the below-described compound (a) is oily matter, from which a crude product (b) is obtained as oily matter by isolating and purifying the oily matter (a) by chromatography on a silica gel column, followed by reductive debenzylation. Chromatography on a silica gel column, however, is not suited for production on an industrial scale. 
wherein Bn means a benzyl group and tBu means a tert-butyl group.
For preparation of various HMG-CoA reductase inhibitors, tert-butyl (3R,5S)-3,5-O-isopropylidene-3,5,6-trihydroxyhexanoate (b) having the 6-hydroxyl group deprotected is a particularly important compound, because the 6-position of the (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative is a bonding site to another compound.
In consideration of the preparation on an industrial scale, it is preferred to isolate and purify the compound formed in each step as highly pure and stable crystals which can be handled easily.
Although reports on the isolation of a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative in the form of crystals are not so many, examples include: 1) U.S. Pat. No. 5,278,313 describes preparation of compounds (c) and (e), which will be described below, in the form of crystals at xe2x88x9220 to xe2x88x925xc2x0 C. It does not include a description on diastereoselectivity. Moreover, no attempt is made to improve the diastereoselectivity by recrystallization. 2) JP-A-2-262537 describes preparation of the below-described compounds (c) and (d) in the form of crystals by isolation and purification through chromatography on a silica gel column. As described above, however, separation by chromatography on a silica gel column is not suited for industrial production. 3) JP-T-6-502162 (the term xe2x80x9cJP-Txe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent application based on International applicationxe2x80x9d) describes isolation of the below-described compound (f) (X=Cl, Br or NO2) as a solid. No attempt, however, is made in order to improve the diastereoselectivity by crystallization. 
wherein Bz represents a benzoyl group, tBu means a tert-butyl group, Ac means an acetyl group and X represents a chlorine atom, a bromine atom or a nitro group.
Although it is essential to improve the diastereoselectivity of a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative for production on an industrial scale, it is the present state that no attempt has been made to improve the diastereoselectivity by crystallization.
An object of the present invention is therefore to prepare, safely in a high yield in a simple manner, a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative which can satisfy the above-described demands, is in the form of crystals permitting easy handling and has high chemical purity.
Under such situations, the present inventors have carried out an extensive investigation with a view to attaining the above-described object. As a result, it has been found that a novel ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative in the form of crystals can be prepared in a high yield by causing a specific amine to act on a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative. It has also been found that isolation and purification of an ammonium derivative in the form of crystals permitting easy handling make it possible to improve the chemical purity of the derivative and that the chemical purity thus attained is markedly high, leading to the completion of the present invention.
The present invention therefore embraces the following aspects.
1) An ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative represented by the following formula (I): 
wherein R1 represents a benzyl group which may have a substituent, a triphenylmethyl group which may have a substituent, an organosilyl group or a C1-5 acyl group; and A represents at least one amine selected from the group consisting of a primary amine represented by the following formula (IIIa):
R2xe2x80x94NH2xe2x80x83xe2x80x83(IIIa)
(in which R2 represents a C1-7 alkyl group or a C5-7 alicyclic group), a primary benzylamine represented by the following formula (IIIb): 
(in which R3 represents a hydrogen atom, a methyl group or a hydroxymethyl group and Ar represents a phenyl group which may have a substituent), a secondary amine represented by the following formula (IIIc): 
(in which R4 and R5 are the same or different and each independently represents a C5-7 alicyclic group), cinchamidine, cinchotine, cinchonamine, cinchonidine and cinchonine.
2) An ammonium (3R,5S)-3,5,6-trihydroxyhexanoate as described above in 1), wherein a ratio of the syn-isomer to the anti-isomer falls within a range of 99.0/1.0 to 100/0.
3) A process for producing an ammonium (3R,5S)-3,5,6-trihydroxyhexanoate in the form of crystals, which comprises causing the amine (A) as described above in 1) to act on a (3R,5S)-3,5,6-trihydroxyhexanoic acid represented by the following formula (II): 
wherein R1 has the same meaning as described above.
4) A process for producing a high-purity ammonium (3R,5S)-3,5,6-trihydroxyhexanoate in the form of crystals, which comprises causing the amine (A) as described above in 1) to act on the (3R,5S)-3,5,6-trihydroxyhexanoic acid represented by the formula (II) and crystallizing the resulting ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative precursor to improve the chemical purity thereof.
The present invention will next be described more specifically.
In the ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative of the invention, R1 represents a benzyl group which may have a substituent, a triphenylmethyl group which may have a substituent, an organosilyl group or a C1-5 acyl group.
Specific examples of R1 include a benzyl group which may have a substituent, for example, a lower C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, a lower C1-4 alkoxy group such as methoxy, ethoxy, propoxy or butoxy, or a halogen atom such as fluorine, chlorine, bromine or iodine; a triphenylmethyl group which may have a substituent, for example, a lower C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, a lower C1-4 alkoxy group such as methoxy, ethoxy, propoxy or butoxy, or a halogen atom such as fluorine, chlorine, bromine or iodine; organosilyl groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, dimethylcumylsilyl, triisopropylsilyl, dimethylthexylsilyl, trimethylsilyl, and dimethylhexylsilyl; C1-5 acyl groups such as formyl, acetyl, propionyl, butyloyl, valeloyl, isovaleloyl and pivaloyl.
Preferred specific examples of R1 include benzyl, triphenylmethyl, tert-butyldimethylsilyl and acetyl groups.
In the ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative (I) of the invention, A represents an amine.
The amine (A) is at least one amine selected from the amines represented by the above-described formulas (IIIa), (IIIb) and (IIIc), cinchamidine, cinchotine, cinchonamine, cinchonidine and cinchonine.
Specific examples of R2 in the formula (IIIa) include C1-7 alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, pentyl, hexyl and heptyl; and C5-7 alicyclic groups such as cyclopentyl, cyclohexyl and cycloheptyl.
Specific examples of Ar in the formula (IIIb) include phenyl groups which may have a substituent such as phenyl, p-tolyl and xylyl.
Specific examples of R4 or R5 in the formula (IIIc) include C5-7 alicyclic groups such as cyclopentyl, cyclohexyl and cycloheptyl.
Specific preferred examples of the amine (A) are as follows: primary amines of the formula (IIIa), for example, alkyl-containing primary amines such as propylamine and tert-butylamine, and alicyclic primary amines such as cyclohexylamine; primary amines of the formula (IIIb), for example, benzyl-containing primary amines such as benzylamine, phenylethylamine and phenylethanolamine; secondary amines of the formula (IIIc), for example, alicyclic secondary amines such as dicyclohexylamine; cinchonidine; and cinchonine. More preferred are primary amines such as propylamine, tert-butylamine, cyclohexylamine, benzylamine, phenylethylamine and phenylethanolamine.
The ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative of the invention is prepared in accordance with the following reaction. 
wherein R1 represents a benzyl group which may have a substituent, a triphenylmethyl group which may have a substituent, an organosilyl group or a C1-5 acyl group and A means an amine.
The ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative (I) is prepared in the form of crystals by causing the above-described amine (A) to act on (3R,5S)-3,5,6-trihydroxyhexanoic acid (II) as a starting material and then, cooling the reaction product.
The (3R,5S)-3,5,6-trihydroxyhexanoic acid (II) to be used in the invention is available by a known manner, for example, that described in JP-A-2-289537 or JP-A-6-65226.
The amine (A) is used in an amount of 1 to 2 times, more preferably 1 to 1.3 times the mole relative to 1 mole of the (3R,5S)-3,5,6-trihydroxyhexanoic acid (II).
As a reaction solvent, usable are those which do not adversely affect the reaction. Examples include esters such as methyl acetate, ethyl acetate, propyl acetate and butyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane and 1,3-dioxolan; ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and cyclohexanone; alcohols such as methanol, ethanol, isopropyl alcohol and butanol; acetonitrile; and water; and mixed solvents thereof.
The above-exemplified solvent is usually employed in an amount of 1 to 100 times the volume, preferably 1 to 50 times the volume, of the mass (or volume) of the (3R,5S)-3,5,6-trihydroxyhexanoic acid (II).
This reaction is usually conducted in an inert gas atmosphere such as nitrogen gas or argon gas. This reaction is usually conducted for about 30 minutes to 10 hours at a temperature of about 20 to 50xc2x0 C. By subsequent stirring at about xe2x88x9220 to 50xc2x0 C. for 1 to 10 hours, reaction is terminated, whereby an ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative (I) can be obtained as crystals. The above-described conditions can be changed as needed, depending on the kind of the amine (A) to be employed.
The ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative (I) of the present invention thus prepared is in the form of crystals as is apparent from Examples which will be described later. Crystallization makes it possible to prepare the derivative at a high selectivity to the syn-isomer [(3R,5S)-isomer] relative to the anti-isomer and even if the preparation ratio of the syn-isomer is insufficient, high-purity syn-isomer [(3R,5S)-isomer] is available by recrystallization. In the invention, a ratio of the syn-isomer to the anti-isomer ranging from 99.0/1.0 to 100/0, preferably 99.1/0.9 to 100/0, more preferably 99.4/0.6 to 100/0 can be attained. Moreover, since the derivative of the present invention is obtained in the form of crystals, it has stability by far superior to that in the oily form.
In consideration of the difficulty in purification of the (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative in the industrial preparation process, the invention, which facilitates the purification by preparing its ammonium salt derivative (I) in the form of crystals, brings about a large merit in the synthesis research of an HMG-CoA reductase inhibitor.